Systemic mastocytosis (SM), a myeloproliferative disorder with variable clinical manifestations, is associated in most cases with the D816V mutation in KIT. The identification of the KIT D816V mutation in patients with systemic mastocytosis has gained a major prognostic significance in the last several years, largely because of the availability of tyrosine kinase receptor inhibitors such as imatinib. However, imatinib is ineffective in patients carrying KIT D816V mutation. In collaboration with Deciphera Pharmaceuticals, we thus evaluated novel KIT switch pocket inhibitors on mast cell proliferation and activation. We found that neoplastic human mast cell lines harboring the KIT D816V mutation were significantly inhibited by the switch pocket inhibitors through the induction of apoptosis. Overall, switch pocket inhibitors thus may provide therapeutic benefit. Because eosinophils are sometimes elevated in patients with mastocytosis, we assessed surface and soluble IL-5R levels in patients with eosinophilia and/or mastocytosis in a collaboration with Dr. Klion's research group. sIL-5R was significantly elevated in patients with systemic mastocytosis without eosinophilia. sIL-5R levels correlated with serum tryptase and eosinophil activation. These data may have implications with respect to the use of novel therapeutic agents targeting IL-5 and its receptor in patients with eosinophilia and/or mastocytosis. KIT has two major variants which differ by four amino acids (GNNK- or GNNK+) at the juxta-membrane region of the extracellular domain. Using a quantitative real-time PCR assay to assess GNNK- and GNNK+ transcripts from the bone marrow mononuclear cells of patients with systemic mastoycytosis, we found that the relative expression of the GNNK- variant strongly correlated with neoplastic mast cell involvement. Using a mast cell transfection system, we have found that he GNNK- variant is associated with increased granule formation, cellular growth and resistance to the tyrosine kinase inhibitors. Studies are underway to better understand the mechanisms behind these observations.